Particle characterization

ABSTRACT

In one general aspect, a method of measuring characteristics of particles in a liquid sample is disclosed. The method includes suspending the liquid sample in a tube. The suspended liquid sample is illuminated along an illumination axis, and at least a portion of the light is detected along a first detection axis after it is scattered by the particles in the suspended liquid sample. The illumination axis and the detection axis are oriented at an angle with respect to each other.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. 119(e) of U.S.provisional application Ser. No. 61,209,139, filed Mar. 4, 2009 andprovisional application Ser. No. 61,209,138, filed Mar. 4, 2009, and itis a continuation of PCT application number PCT/GB2010/050382, filedMar. 4, 2010 and PCT application number PCT/GB2010/050383, filed Mar. 4,2010. It is also related to U.S. nonprovisional application Ser. No.12/717,900 entitled PARTICLE CHARACTERIZATION, filed today. All of theserelated applications are herein incorporated by reference.

FIELD OF THE INVENTION

This invention relates to methods and apparatus for detectingcharacteristics of particles suspended in a liquid sample, such asthrough the use of Static Light Scattering (SLS) and/or Dynamic LightScattering (DLS) measurements.

BACKGROUND OF THE INVENTION

SLS and DLS measurements are typically performed using cuvettes withhigh-quality optical surfaces, which can be glass, in order to reducescattering from static surfaces. These can be relatively expensive, andthey can use a relatively large amount of sample material. It is alsodifficult to clean off residue from some types of samples, such asproteins.

SUMMARY OF THE INVENTION

In one general aspect, the invention features a method of measuringcharacteristics of particles in a liquid sample that includes suspendingthe liquid sample in a tube. The suspended liquid sample is illuminatedalong an illumination axis, and at least a portion of the light isdetected along a first detection axis after it is scattered by theparticles in the suspended liquid sample. The illumination axis and thedetection axis are oriented at an angle with respect to each other.

In preferred embodiments, the liquid sample can be suspended in a tubewith a removable cover. The liquid sample can be suspended in the tubeby atmospheric pressure. The liquid sample can be suspended in the tubeby a sealed upper surface hydraulically connected to the cavity. Thesealed upper surface can be a surface of a piston. The liquid sample canbe suspended by a pumping action. The method can further include stepsof storing capillary tubing with the instrument and cutting the tubefrom the stored capillary tubing before the step of suspending thesample in the tube. The method can further include the step of cuttingthe tube from a length of capillary tubing before the step ofsuspending, with a same user performing both the step of cutting and thestep of suspending. The step of providing can provide a capillary tubethat is made of glass. The step of providing can provide a capillarytube that is made of plastic. The step of introducing the sample canintroduce less than about 50 μl of liquid into the tube. The step ofintroducing the sample can introduce less than about 10 μl of liquidinto the tube. The step of introducing the sample can introduce lessthan about 1 μl of liquid into the tube. The method can further includethe step of disposing of the tube, and repeating the steps of receiving,suspending, illuminating, detecting, and disposing for further sampleswith new tubes for each of the further samples. The step of disposingcan dispose of the tube and the sample at the same time. The method canfurther include the step of removing the sample from the tube before thestep of disposing of the tube. The method can further include the stepof causing the liquid sample to flow through the tube to a detectionposition before the step of detecting. The method can further includefurther steps of causing further samples to flow through the tube andfurther steps of detecting that each take place after one of the furthersteps of causing samples to flow. The step of causing the liquid to flowthrough the tube can be performed continuously. The method can furtherinclude further steps of causing further samples to flow throughadditional tubes and further steps of detecting that each take placeafter one of the further steps of causing samples to flow, with thesteps of causing samples to flow being performed through disposabletubes, and the method can further include steps of disposing of thetubes between at least some of the steps of detecting.

In another general aspect, the invention features an instrument formeasuring light scattered by particles in a liquid sample that includesa light source having an optical light output axis, a tube holder for atube that includes means for suspending the liquid sample, positioned inthe light output axis of the light source, and at least one scatteredlight detector, positioned to receive scattered light from the tubealong an axis that is oriented at an angle with respect to the lightoutput axis of the light source.

In preferred embodiments the instrument can further include an integralcapillary cutting implement. The capillary cutting implement ispositioned to allow the capillary tube to be cut while it is positionedin the holder along the light output axis of the light source. Thecapillary cutting implement can include a stationary blade attached tothe capillary holder. The holder can be part of a removable capillarycarrier that can be removed from the instrument. The capillary tubeholder can be operative to hold a capillary tube that has a squarecross-section. The capillary tube holder can be operative to hold acapillary tube that has a round cross-section. The method can furtherinclude a capillary tube held by the holder. The capillary tube can bemade of glass. The capillary tube can be made of plastic. The capillarytube can be sealed at one or both ends. The tube holder can be operativeto hold a tube that holds less than about 50 μl of liquid. The tubeholder can be operative to hold a tube that holds less than about 10 μlof liquid. The tube holder can be operative to hold a tube that holdsless than about 1 μl of liquid. The holder can be constructed andadapted to hold a tube that has an internal diameter of about 2 mm orless in the optical light output axis of the light source, with theinternal diameter of the capillary tube constituting the means forsuspending the liquid sample. The tube holder can be operative to hold atube that is 0.5 mm in diameter or less. The apparatus can furtherinclude a pair of hydraulic fittings to hydraulically connect the tubeto a process flow. The apparatus can further include at least a secondscattered light detector positioned to receive scattered light from thetube along another angle with respect to the light output axis of thelight source.

In a further general aspect, the invention features an instrument formeasuring light scattered by particles in a liquid sample that includesa light source having an optical light output axis, a capillary tubeholder for a capillary tube positioned in the light output axis of thelight source, wherein the holder is constructed and adapted to hold acapillary tube that has an internal diameter of about 2 mm or less inthe optical light output axis of the light source, and at least onescattered light detector, positioned to receive scattered light from thecapillary tube along an axis that is oriented at an angle with respectto the light output axis of the light source.

In another general aspect, the invention features a method of measuringscattered light from particles in a liquid sample that includesreceiving a new length of capillary tube, introducing the sample intothe length of capillary tube, illuminating the sample in the capillarytube, detecting at least a portion of the light after it is scattered bythe particles in the sample, disposing of the capillary tube, andrepeating the steps of receiving, introducing, illuminating, detecting,and disposing for further samples with new tubes for each of the furthersamples.

In a further general aspect, the invention features a method ofmeasuring characteristics of particles in a liquid sample, that includessupporting the liquid sample by atmospheric pressure, illuminating thesupported liquid sample along an illumination axis, and detecting atleast a portion of the light along a first detection axis after it isscattered by the particles in the supported liquid sample, wherein theillumination axis and the detection axis are oriented at an angle withrespect to each other. In preferred embodiments the liquid sample can besupported in a capillary tube with a removable cover.

In another general aspect, the invention features an instrument formeasuring characteristics of particles in a liquid sample that includesa cavity for holding the liquid sample, a sealed upper surfacehydraulically connected to the cavity, a light source having anillumination axis directed through the cavity, and at least onescattered light detector positioned to receive light scattered by theparticles in the liquid sample along a first detection axis that isoriented at an angle with respect to the light output axis of the lightsource when the liquid sample is trapped in the cavity. In preferredembodiments the cavity can be defined by a tube. The sealed uppersurface can be provided by a removable cover.

In a further general aspect, the invention features a method ofmeasuring characteristics of particles in a liquid sample that includescausing the liquid sample to flow through a capillary tube, illuminatingthe flowing liquid sample through a wall of the capillary tube along anillumination axis, and detecting at least a portion of the light along afirst detection axis after it is scattered by the particles in theflowing liquid sample, wherein the illumination axis and the detectionaxis are oriented at an angle with respect to each other.

In preferred embodiments the method can further include further steps ofcausing the sample to flow through the capillary tubes and further stepsof detecting that each take place after one of the further steps ofcausing the sample to flow. The steps of causing the liquid to flowthrough the capillary tube can be performed through disposablecapillaries and the method can further include steps of disposing of thedisposable capillaries between at least some of the measurements. Thestep of causing the liquid to flow through the capillary tube can beperformed continuously.

In another general aspect, the invention features an instrument formeasuring characteristics of particles in a liquid sample that includesan open length of capillary tube having a first open end and a secondopen end, an input hydraulic connection between the first end and aprocess flow output, an output hydraulic connection between the secondend and a process flow input, a light source having an illumination axisdirected through the capillary tube, and at least one scattered lightdetector positioned to receive light scattered by the particles in theliquid sample along a first detection axis that is oriented at an anglewith respect to the light output axis of the light source when theliquid sample is trapped in the cavity.

In a further general aspect, the invention features a method ofmeasuring characteristics of particles in a liquid sample that includessupporting the liquid sample by surface tension and illuminating thesupported liquid sample along an illumination axis with spatiallycoherent light so as to cause the coherent light to be scattered acrossa scattering zone. At least a portion of the scattered light is detectedalong a first predetermined scattering detection axis after it isscattered by the particles in the supported liquid sample. Theillumination axis and the detection axis are oriented at an angle withrespect to each other that allows substantially all of the lightscattered at that angle across the scattering zone to be detected.

In preferred embodiments the method can further include the step ofderiving a dynamic light scattering measurement for a predeterminedangular resolution from results of the step of detecting. The method canfurther include the step of deriving a static light scatteringmeasurement for a predetermined angular resolution from results of thestep of detecting. The liquid sample can be supported in a gap definedby two wicking surfaces. The step of illuminating can be performedthrough a supporting surface on the sample. The step of illuminating canbe performed through an unsupported surface on the sample. The step ofdetecting can be performed through a supporting surface on the sample.The step of detecting can be performed through an unsupported surface onthe sample. The method can include further steps of detecting alongfurther detection axes that are oriented at further angles with respectto the illumination axis. The step of supporting can include supportingthe sample in a sample carrier, with the method further including thestep of positioning the sample carrier so that the first optical axisintersects the sample. The step of detecting can detect backscatteredlight. The step of illuminating can illuminate the trapped liquid samplewith at least partially coherent light. The step of illuminating canilluminate the trapped liquid sample with coherent light. The step ofdetecting can detect time-averaged scattered light for a sample. Thestep of detecting can detect time-dependent scattered light for asample.

In another general aspect, the invention features an instrument formeasuring characteristics of particles in a liquid sample that includesone or more wicking surfaces and a spatially coherent light sourcehaving an illumination axis directed proximate the wicking surfaces soas to cause coherent light from the source to be scattered across ascattering zone. At least one spatially coherent scattered lightdetector is positioned to receive light scattered by the particles inthe liquid sample along a first predetermined scattering detection axisthat is oriented at an angle with respect to the illumination axis ofthe light source when the liquid sample is trapped by the wickingsurfaces. The angle between the predetermined scattering detection axisand the illumination axis allows the detector to detect substantiallyall of the coherent light scattered at that angle across the scatteringzone.

In preferred embodiments one or more of the wicking surfaces are eachpart of one or more transparent optical parts. The source can bepositioned to direct light through a first of the wicking surfaces. Thedetector can be positioned to receive scattered light through a first ofthe wicking surfaces. The source can be positioned to direct lighttoward a position on a surface of the trapped sample that does not toucheither of the wicking surfaces. The detector can be positioned toreceive scattered light from a position on a surface of the trappedsample that does not touch either of the wicking surfaces. The detectorcan be positioned to receive backscattered light from the sample. Thefirst wicking surface can be part of a first transparent optical partand the second wicking surface can be part of a second transparentoptical part that is separate from the first transparent optical part.The apparatus can further include a supporting body positioned to holdthe wicking surfaces in place. The supporting body can be part of aremovable sample carrier that can be removed from the instrument. Therecan be four wicking surfaces for a single sample. All four of thewicking surfaces can each be part of a transparent optical part. Theillumination axis of the light source can pass through the samplewithout passing through any of the wicking surfaces. A gap can definedby the wicking surfaces can be sized to hold an aqueous sample betweenthe first wicking surface and the second wicking surface by surfacetension. The first and second wicking surfaces can be parallel to eachother. The first and second wicking surfaces can be positioned at anangle, which can be equal to a scattering angle between the illuminationaxis of the light source and the detection axis of the detector. Thelight source can be a laser.

In a further general aspect, the invention features a method ofmeasuring characteristics of particles in a liquid sample that includessupporting the liquid sample by surface tension over at least onesupported surface, illuminating the supported liquid sample through thesupported surface of the liquid along an illumination axis, anddetecting at least a portion of the light along a first scatteringdetection axis after it is scattered by the particles in the supportedliquid sample, wherein the illumination axis and the detection axis areoriented at an angle with respect to each other.

In another general aspect, the invention features an instrument formeasuring characteristics of particles in a liquid sample that includesone or more wicking surfaces, a light source having an illumination axisdirected through at least one of the wicking surfaces, and at least onescattered light detector positioned to receive light scattered by theparticles in the liquid sample along a first scattering detection axisthat is oriented at an angle with respect to the illumination axis ofthe light source when the liquid sample is trapped by the wickingsurfaces.

In a further general aspect, the invention features a method ofmeasuring characteristics of particles in a liquid sample that includessupporting the liquid sample by surface tension over at least onesupported surface, illuminating the supported liquid sample along anillumination axis, and detecting at least a portion of the light throughan unsupported surface of the liquid along a first scattering detectionaxis after it is scattered by the particles in the supported liquidsample, wherein the illumination axis and the detection axis areoriented at an angle with respect to each other.

In another general aspect, the invention features an instrument formeasuring characteristics of particles in a liquid sample that includesone or more wicking surfaces, a light source having an illumination axisdirected proximate the wicking surfaces, and at least one scatteredlight detector positioned to receive light scattered by the particles inthe liquid sample through a surface that is unsupported by the wickingsurfaces along a first scattering detection axis that is oriented at anangle with respect to the illumination axis of the light source when theliquid sample is trapped by the wicking surfaces.

Measurement systems according to the invention can perform scatteringmeasurements quickly and efficiently. By holding a small drop of samplefluid in the path of an incident beam, scattering measurements for oneor more scattering modes can be performed on a very small sample. Thecomponents used to hold the samples can then be disposed of or easilycleaned. The use of separate wicking surfaces to support samples allowsfor easy cleaning of surfaces, and these may even be provided on adisposable optical element. Capillary tubes can hold a very small amountof liquid for scattering measurements and then be discarded.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a series of diagrams illustrating the use of opticalcomponents to trap sample droplets in various static and dynamic lightscattering measurement configurations with one or two-face opticallayouts;

FIG. 2 is diagram illustrating the use of optical components to trap asample droplet in a dynamic light scattering measurement configurationwith a multiple-face optical layout;

FIG. 3A is an isometric projection of a holder for use with lightscattering measurement configurations such as those shown in FIG. 1;

FIG. 3B is a cross-sectional view of the holder of FIG. 3A that usesNIBS to position crossover of an incident beam;

FIG. 3C is a cutaway view of the holder of FIG. 3A;

FIG. 4 is a three-view drawing of the holder showing illustrativeoverall dimensions to fit in commonly found cuvette holders;

FIG. 5A is a diagram showing a sample trapped by surface tension withina capillary;

FIG. 5B is a diagram of a sample trapped by atmospheric pressure via apinched top;

FIG. 5C is a diagram of a sample trapped by atmospheric pressure via asealed top;

FIG. 5D is a diagram of a sample trapped within a capillary as part of aflow path;

FIG. 6 is a cross-sectional diagram showing an optical geometry for acapillary tube;

FIG. 7A is an illustrative implementation of a capillary carrierincluding a slot at the top to trap and seal a flexible tube (attachedto the top end of the capillary) for atmospheric trapping of sample asshow in FIG. 5B;

FIG. 7B is an illustrative implementation of a capillary carrierincluding a capillary cutter 44; and

FIG. 8 is three-view drawing of the capillary carrier of FIG. 7A holdershowing illustrative overall dimensions to fit in commonly found cuvetteholders.

DETAILED DESCRIPTION OF AN ILLUSTRATIVE EMBODIMENT

Referring to FIG. 1, an illustrative embodiment of a particlecharacteristics measuring instrument can perform trapped droplet samplepresentation for static and dynamic light scattering instruments inforward, side and backscatter.

S/DLS measurements can require very small sample volumes to reducecosts. Further, S/DLS measurements require very high optical qualitysurfaces in order to reduce scattering from static surfaces, precludingthe use of low optical quality disposable plastic cells. Further still,proteins, for example, are often very difficult to clean from glasscuvettes that are typically quite deep and prevent the entry ofmechanical cleaning devices, such as brushes.

In instruments according to the invention, however, a sample droplet 10is placed on a lower optical surface 12—see FIG. 1( a). In oneembodiment, the incident light beam 16 and detected light beam 18intersect within the droplet, with the droplet in contact only with thelower surface. In another embodiment the upper optical surface 14 ismoved down until it makes contact with the sample—FIG. 1( b,c,d). Thesample droplet wicks onto the upper surface, whilst remaining attachedto the lower surface. The sample is trapped by surface tension. Theupper surface is then drawn up to create a sample bridge within whichthe incident and detection beams can intersect. The distance between theoptical surfaces would typically be of the order of 1-2 mm. The positionof the crossover (intersection of incident and detected light beams)within the trapped droplet can be set via separate optics: i.e.independently of the position of the optical surfaces. e.g. inbackscatter via NIBS technology (described in U.S. Pat. No. 6,016,195which is herein incorporated by reference)—see FIG. 3 for example. Thesample may also be trapped between more than two surfaces e.g. see FIG.2 (12, 14, 22, 24), and opposing surfaces may be non-parallel—FIG. 1(d). The surfaces exposed to the sample may be any shape deemedconvenient and/or necessary for efficient trapping of the sample viasurface tension and/or optical deviation and focusing of the incidentand detected beams.

In FIG. 1( b), the light enters the droplet 10 through one of theoptical surfaces at some appropriate, well-defined angle and is detectedin either forward 18F or backscatter 18B (again at some appropriateangle) through the optical surfaces or at a higher angle (typically, butnot exclusively, 90 degrees to the input beam 18S) through the dropletside. In FIG. 1( c) the beam enters through the side of the droplet andis detected through either or both of upper and lower optical surfacesor through the droplet side.

In all proposed cases, FIG. 1( a)-(d), all optical beams (incident anddetected) should have a well defined angle with respect to each otherand should be pseudo-monochromatic, with centre wavelength, λ. The ISOstandard for DLS (ISO 22412) states that the reported size should be+/−2% of the validated value of a standard sample. The Cumulantsanalysis is the standard basic reduction and it equates the measuredquantity, g1, the correlation function, to the fit,

$\begin{matrix}{{g^{1}\left( {q,\tau} \right)} = {{\exp \left( {- {\Gamma\tau}} \right)}\left( {1 + {\frac{\mu^{2}}{2!}\tau^{2}} + \ldots}\mspace{14mu} \right)}} & (1)\end{matrix}$

Γ, is related to the diffusion coefficient, D via the q vector by

$\begin{matrix}{{\Gamma = {q^{2}D}}{where}} & (2) \\{q = {\frac{4\pi \; n}{\lambda}{\sin \left( \frac{\theta}{2} \right)}}} & (3)\end{matrix}$

In which θ is the angle between the incident and detected beams. n, isthe refractive index of the dispersant in which the particles aredispersed. The particle radius, r, is then related to the diffusioncoefficient via the Stokes-Einstein relation

$\begin{matrix}{D = \frac{k_{B}T}{6\pi \; {nr}}} & (4)\end{matrix}$

Where, k_(B) is the Boltzmann constant and T is the temperature. Via Eq.(2), q² should be defined to <2% to meet the ISO standard and thence θto within 1.414=√{square root over (2≦1.5)}%. We should also, then,define λ to <2% for DLS. The requirements of SLS are a subset of θ+/−1.5% and λ +/−2%.

One embodiment of the scheme is shown in FIG. 3. The entire apparatuscan fit inside the cuvette holder 30 of a Zetasizer Nano particlecharacterization instrument underneath the thermal cap in order toprovide degree of thermal control appropriate to S/DLS. The ZetasizerNano particle characterization instrument is available from MalvernInstruments of Malvern, UK, and is discussed in more detail in U.S.application Nos. 61/206,688 and 61/195,647, which are hereinincorporated by reference.

Once measured the sample can be re-pipetted for further use and anymaterial left on the optical surfaces removed with easy access.

Another approach involves a semi disposable sample presentation schemefor the measurement of dynamic and static light scattering for size andmolecular weight determination in forward, side and backscatter. Thisscheme can allow for presentation of very small sample volumes to D/SLSinstruments in an easy to use and semi-disposable format.

Good optical quality glass or plastic capillary tubing is availablerelatively cheaply now and the following scheme is proposed—FIG. 5. Alength of capillary 40 is held in place (as required by the opticalgeometry of the instrument) and the tube filled from either end byattached tube or a pipette. The sample is retained by one of threemechanisms. In the first instance, the capillary is small enough to trapthe sample by surface tension with the other end of the capillary leftopen to atmosphere—FIG. 5( a)—for example. In the second instance, thetop of the capillary is sealed by some means—FIG. 5( b) and FIG. 5( c)for example—so that the sample is trapped within the capillary byatmospheric pressure at the capillary bottom (sample end in FIG. 5). Inthe third instance, the capillary forms part of a flow circuit—FIG. 5(d) for example.

The incident light beam may enter the sample through any side face ofthe capillary—FIG. 6. One or more detection beams may also exit the cellthrough any or all of the side faces of the capillary.

The capillary 40 is held in place by a carrier 42—FIG. 7, which is thenlocated into the instrument. The dimensions of the carrier match thoseof a standard cuvette, such that it enables use in an instrument inwhich standard cuvettes are used. Typical dimensions of such a carrierare shown in FIG. 8. A device for cutting the capillary to length whilstfitting into the carrier is also proposed, an example of which is shownin FIG. 7( b). Once in place the sample is pippetted into the bottom ofthe capillary as shown in FIG. 5—the large hole in the base of thecarrier—FIG. 7—is included for this purpose. Once the measurement iscomplete the sample may then be re-pippetted out of the capillary forfurther analysis.

If the capillary becomes dirty in use it may be cheaply disposed of anda new one fitted for further measurements. Capillaries of 0.5 mminternal dimensions and smaller are readily available thereby allowingconvenient, semi-disposable measurement volumes of 10's to 100's ofnanolitres for the first time.

Referring to FIG. 9, a piston 50 or other pumping mechanism may beprovided to draw a precise amount of a liquid sample into a capillarytube, hold it (if necessary), and then expel it (if necessary). The useof a piston can allow even a very small drop to be positioned preciselywithin a capillary tube in the path of an incident beam. The piston maybe advanced by a screw, a motor, or another suitable mechanism.

The present invention has now been described in connection with a numberof specific embodiments thereof. However, numerous modifications whichare contemplated as falling within the scope of the present inventionshould now be apparent to those skilled in the art. Therefore, it isintended that the scope of the present invention be limited only by thescope of the claims appended hereto. In addition, the order ofpresentation of the claims should not be construed to limit the scope ofany particular term in the claims.

1. A method of measuring characteristics of particles in a liquidsample, comprising: suspending the liquid sample in a tube, illuminatingthe suspended liquid sample along an illumination axis, and detecting atleast a portion of the light along a first detection axis after it isscattered by the particles in the suspended liquid sample, wherein theillumination axis and the detection axis are oriented at an angle withrespect to each other.
 2. The method of claim 1 wherein the liquidsample is suspended in a tube with a removable cover.
 3. The method ofclaim 1 wherein the liquid sample is suspended in the tube byatmospheric pressure.
 4. The method of claim 1 wherein the liquid sampleis suspended in the tube by a sealed upper surface hydraulicallyconnected to the cavity.
 5. The method of claim 4 wherein the sealedupper surface is a surface of a piston.
 6. The method of claim 1 whereinthe liquid sample is suspended by a pumping action.
 7. The method ofclaim 1 further including steps of storing capillary tubing with theinstrument and cutting the tube from the stored capillary tubing beforethe step of suspending the sample in the tube.
 8. The method of claim 1further including the step of cutting the tube from a length ofcapillary tubing before the step of suspending, wherein a same userperforms both the step of cutting and the step of suspending.
 9. Themethod of claim 1 wherein the step of providing provides a capillarytube that is made of glass.
 10. The method of claim 1 wherein the stepof providing provides a capillary tube that is made of plastic.
 11. Themethod of claim 1 wherein the step of introducing the sample introducesless than about 50 μl of liquid into the tube.
 12. The method of claim 1wherein the step of introducing the sample introduces less than about 10μl of liquid into the tube.
 13. The method of claim 1 wherein the stepof introducing the sample introduces less than about 1 μl of liquid intothe tube.
 14. The method of claim 1 further including the step ofdisposing of the tube, and repeating the steps of receiving, suspending,illuminating, detecting, and disposing for further samples with newtubes for each of the further samples.
 15. The method of claim 14wherein the step of disposing disposes of the tube and the sample at thesame time.
 16. The method of claim 14 further including the step ofremoving the sample from the capillary tube before the step of disposingof the tube.
 17. The method of claim 1 further including the step ofcausing the liquid sample to flow through the tube to a detectionposition before the step of detecting.
 18. The method of claim 17further including further steps of causing further samples to flowthrough the tube and further steps of detecting that each take placeafter one of the further steps of causing samples to flow.
 19. Themethod of claim 18 wherein the step of causing the liquid to flowthrough the tube is performed continuously.
 20. The method of claim 17further including further steps of causing further samples to flowthrough additional tubes and further steps of detecting that each takeplace after one of the further steps of causing samples to flow, whereinthe steps of causing samples to flow are performed through disposabletubes, and further including steps of disposing of the tubes between atleast some of the steps of detecting.
 21. An instrument for measuringlight scattered by particles in a liquid sample, comprising: a lightsource having an optical light output axis, a tube holder for a tubethat includes means for suspending the liquid sample, positioned in thelight output axis of the light source, and at least one scattered lightdetector, positioned to receive scattered light from the tube along anaxis that is oriented at an angle with respect to the light output axisof the light source.
 22. The apparatus of claim 21 wherein theinstrument further includes an integral capillary cutting implement. 23.The apparatus of claim 22 wherein the capillary cutting implement ispositioned to allow the capillary tube to be cut while it is positionedin the holder along the light output axis of the light source.
 24. Theapparatus of claim 23 wherein the capillary cutting implement includes astationary blade attached to the capillary holder.
 25. The apparatus ofclaim 24 wherein the holder is part of a removable capillary carrierthat can be removed from the instrument.
 26. The apparatus of claim 21wherein the holder is part of a removable capillary carrier that can beremoved from the instrument.
 27. The apparatus of claim 21 wherein thecapillary tube holder is operative to hold a capillary tube that has asquare cross-section.
 28. The apparatus of claim 21 wherein thecapillary tube holder is operative to hold a capillary tube that has around cross-section.
 29. The apparatus of claim 21 further including acapillary tube held by the holder.
 30. The apparatus of claim 29 whereinthe capillary tube has a square cross-section.
 31. The apparatus ofclaim 29 wherein the capillary tube is made of glass.
 32. The apparatusof claim 29 wherein the capillary tube is made of plastic.
 33. Theapparatus of claim 29 wherein the capillary tube has a roundcross-section.
 34. The apparatus of claim 29 wherein the capillary tubeis sealed at one or both ends.
 35. The apparatus of claim 21 wherein thetube holder is operative to hold a tube that holds less than about 50 μlof liquid.
 36. The apparatus of claim 21 wherein the tube holder isoperative to hold a tube that holds less than about 10 μl of liquid. 37.The apparatus of claim 21 wherein the tube holder is operative to hold atube that holds less than about 1 μl of liquid.
 38. The apparatus ofclaim 21 wherein the holder is constructed and adapted to hold a tubethat has an internal diameter of about 2 mm or less in the optical lightoutput axis of the light source, and wherein the internal diameter ofthe capillary tube constitutes the means for suspending the liquidsample.
 39. The apparatus of claim 38 wherein the tube holder isoperative to hold a tube that is 0.5 mm in diameter or less.
 40. Theapparatus of claim 21 further including a pair of hydraulic fittings tohydraulically connect the tube to a process flow.
 41. The apparatus ofclaim 21 further including at least a second scattered light detectorpositioned to receive scattered light from the tube along another anglewith respect to the light output axis of the light source.